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\begin{document}

\title{Renal Dysfunction Predicts Major Adverse Cardiovascular Events in Black
and Latino Patients Who Have Atrial Fibrillation}



\author[1]{Muhammad  Zeeshan}%
\author[1]{Eric Lehman}%
\author[1]{Gerald Naccarelli}%
\author[1]{Tariq Ahmad}%
\author[2]{Raji Ayinla}%
\author[1]{Sudhanshu Bhatnagar}%
\affil[1]{Penn State Health Milton S Hershey Medical Center}%
\affil[2]{Harlem Hospital Center}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Atrial Fibrillation (AF) is present in over 6 million
Americans. However, AF occurs less commonly in African Americans and
Latinos compared to Caucasians. Major adverse cardiovascular events
(MACE) is the leading cause of death in these populations. Hypothesis:
We theorize that glomerular filtration rates (GFR) is an independent
risk factor for MACE in African Americans and Latinos with non-valvular
AF (NVAF). Methods: The association of reduced GFR with MACE in NVAF
patients was investigated by retrospective chart review. 656 patients
were included: 339 with GFR \textless{}60 and 317 with GFR [?]60. A
Chi-square test, two-sample t-test, or Wilcoxon Rank Sum test was used
to test for differences between the two groups in terms of demographic
variables and other risk factors. The association between GFR groups and
myocardial infarction (MI), stroke, and/or death, was tested using
binomial logistic regression. To incorporate the element of time and
adjust for covariates, a Cox proportional hazards model analysis was
applied for each outcome variable. Results: As compared to GFR [?]60, a
GFR \textless{}60 in NVAF was an independent risk factor for MI (HR 1.88
(1.17, 3.04); p=0.009); death (HR 1.63 (1.11, 2.41); p=0.014) and MI,
stroke or death ((HR 1.37 (1.05, 1.78); p=0.018). GFR \textless{}60 was
not an independent risk factor for stroke (HR 1.13 (0.77, 1.65);
p=0.529) Conclusion: Renal dysfunction in patients with NVAF is an
independent risk factor for MI, death in and composite of MI, stroke and
death in African American and Latino populations.%
\end{abstract}%



\sloppy


\textbf{Renal Dysfunction Predicts Major Adverse Cardiovascular Events
in Black and Latino Patients Who Have Atrial Fibrillation}

Muhammad Zeeshan, MD. A

Erik B. Lehman, MS. b

Gerald V. Naccarelli, MD. c

Tariq Ali Ahmad MD. d

Raji Ayinla, MD. e

Sudhanshu Bhatnagar, MD. f

\begin{enumerate}
\tightlist
\item
  500 University Drive, Hershey, PA 17033. Department of Medicine, Penn
  State Hershey Medical Center; mzeeshan@pennstatehealth.psu.edu
\item
  500 University Drive, Hershey, PA 17033. Department of Public Health
  Sciences, Penn State College of Medicine;
  elehman@pennstatehealth.psu.edu
\item
  500 University Drive, Hershey, PA 17033. Penn State Heart and Vascular
  Institutue, Penn State Hershey Medical Center;
  gnaccarelli@pennstatehealth.psu.edu
\item
  500 University Drive, Hershey, PA 17033. Penn State Heart and Vascular
  Institutue, Penn State Hershey Medical Center; dogar100@gmail.com
\item
  3184 Grand Concourse, The Bronx, NY 10458. Department of Medicine,
  Harlem Hospital New York, NY mzeeshan198@gmail.com
\item
  500 University Drive, Hershey, PA 17033. Department of Medicine, Penn
  State Hershey Medical Center; ashubhatnagar29@gmail.com
\end{enumerate}

\textbf{Keywords:} Atrial fibrillation, renal dysfunction

\textbf{Correspondence:}

Sudhanshu Bhatnagar 500 University Drive Hershey, PA 17033

Email: ashubhatnagar29@gmail.com

\textbf{Conflicts of interest:} Dr. Naccarelli has research support from
Janssen, unrelated to this paper and is a consultant to Janssen,
Milestone, Omeicos, Sanofi, and Acesion. Remaining authors have no
conflicts of interest to disclose.

\textbf{Funding:} None

\textbf{Disclosure:} None

\textbf{Abstract}

\textbf{Background:} Atrial Fibrillation (AF) is present in over 6
million Americans. However, AF occurs less commonly in African Americans
and Latinos compared to Caucasians. Major adverse cardiovascular events
(MACE) is the leading cause of death in these populations.

\textbf{Hypothesis} : We theorize that glomerular filtration rates (GFR)
is an independent risk factor for MACE in African Americans and Latinos
with non-valvular AF (NVAF).

\textbf{Methods:} The association of reduced GFR with MACE in NVAF
patients was investigated by retrospective chart review. 656 patients
were included: 339 with GFR \textless{}60 and 317 with GFR [?]60. A
Chi-square test, two-sample t-test, or Wilcoxon Rank Sum test was used
to test for differences between the two groups in terms of demographic
variables and other risk factors. The association between GFR groups and
myocardial infarction (MI), stroke, and/or death, was tested using
binomial logistic regression. To incorporate the element of time and
adjust for covariates, a Cox proportional hazards model analysis was
applied for each outcome variable.

\textbf{Results:} As compared to GFR [?]60, a GFR \textless{}60 in NVAF
was an independent risk factor for MI (HR 1.88 (1.17, 3.04); p=0.009);
death (HR 1.63 (1.11, 2.41); p=0.014) and MI, stroke or death ((HR 1.37
(1.05, 1.78); p=0.018). GFR \textless{}60 was not an independent risk
factor for stroke (HR 1.13 (0.77, 1.65); p=0.529)

\textbf{Conclusion} : Renal dysfunction in patients with NVAF is an
independent risk factor for MI, death in and composite of MI, stroke and
death in African American and Latino populations.

Abbreviations: GFR: Glomerular filtration rate; MACE: Major adverse
cardiovascular events; MI: Myocardial Infarction; HR: Hazard ratio;
NVAF: Non-valvular atrial fibrillation

Atrial Fibrillation (AF) is the most prevalent sustained cardiac
arrhythmia disorder. More than 6 million Americans have AF and the
number of cases is expected to rise to double over the next 30 years
(1). Multiple studies have demonstrated that African Americans and
Latinos have a lower prevalence of AF despite having a higher burden of
traditional AF risk factors when compared with Caucasians (2-5). These
minority populations are often underrepresented in large scale AF trials
such as AFFIRM (6). Whereas AF prevalence in the overall general
population averages about 2\%, the estimated prevalence of AF among
patients with renal impairment has been reported up to 23\% depending
upon age, degree of renal impairment and method of detection for AF
(7-9). Thus, there exists a large group of patients that have AF with
reduced glomerular filtration rate (GFR). A unique association between
AF and chronic kidney disease (CKD) is that they share similar risk
factors and comorbidities. (9-17). Non-valvular atrial fibrillation
(NVAF) is an independent risk factor for cardiovascular morbidity and
mortality including death (18, 19), myocardial infarction (MI) (20) and
stroke. Specific risk factors have been identified which significantly
increase the risk of major adverse cardiovascular events (MACE) in
general population with NVAF, as delineated by the
CHA\textsubscript{2}DS\textsubscript{2}VASc score (19, 21). However, the
c statistic for such scoring systems are in the 0.6 range (19). Adding
renal dysfunction to such scoring scales has also been shown to improve
the positive predictive value of this scoring system (22).

It is not clear that white race confers higher AF risk or that African
American and Latino race provide some form of arrhythmia protection.
Renal dysfunction as defined by a GFR \textless{}60 is recognized as an
independent risk factor for MACE (23-27). Traditional risk factors for
MACE are more commonly seen in patients with reduced GFR and AF. There
is minimal published data that establishes CKD as an independent risk
factor for MACE in the African American and Latino AF population. We
conducted a retrospective study, in a unique hospital population mainly
of African Americans and Latinos, to investigate if reduced GFR is an
independent risk factor for MACE primarily in a minority NVAF
population.

\emph{Methods}

A retrospective review of the patients admitted to a single center from
2005 to 2012 was performed.~ All patients with NVAF were selected who
were on guideline directed anticoagulation therapy with warfarin (prior
to approval of novel anticoagulants). Demographic, comorbidity and
medical therapy data were collected and analyzed from a total sample
size of 656 patients, Renal dysfunction was defined as GFR of
\textless{}60 ml/min (339 patients), The MDRD method was used to
calculate GFR. The patient group with GFR \textless{}60 ml/min was not
further categorized into subgroups.

The selected cardiovascular outcomes of interest were myocardial
infarction (MI), stroke (CVA), and death. MI was defined as NSTEMI type
1 or STEMI confirmed by in house cardiologist or by subsequent cardiac
catheterization or a nuclear stress test. Patient with minimal troponin
elevations in settings of demand ischemia were not labelled as having
MI. Stroke was defined as radiographic evidence of non-hemorrhagic
stroke or TIA confirmed by board certified neurologist at the time of
discharge with the help of supporting studies done during the admission.
Manual review of EMR was performed for all patients included in the
study to avoid false positives and negatives.

All statistical analyses were performed with SAS version 9.4 (SAS
Institute, Cary, NC), and statistical significance was set at 0.05. To
check the distributions of all variables prior to analysis, categorical
variables were summarized with frequencies and percentages while
continuous variables were summarized with means, standard deviations,
and medians and with histograms and normal probability plots. A
Chi-square test, two-sample t-test, or Wilcoxon Rank Sum test was used
to test for differences between the group of patients with renal
dysfunction and the group of patients with GFR [?]60 ml/min (Table 1) in
terms of demographic variables and other risk factors.

The association between GFR groups and myocardial infarction, stroke,
death, or any of those events was tested using binomial logistic
regression (Table 2).

To incorporate the element of time and adjust for covariates, a Cox
proportional hazards model analysis was applied for each outcome
variable (Table 3).

The time to the event was calculated as the time from the date of
admission to the time of the event, or time of the first event in the
case of the combination of all events, for patients who had an event and
as the time from the date of admission to the end of the retrospective
study period (12-31-2013) for patients who had no event over the course
of the study period. Potential covariates were determined via a
bivariate analysis of the variables listed in Table 1 with each outcome
variable. Variables with a p-value \textless{}0.10 were included for
model selection. Prior to model selection, the potential covariates were
tested for multicollinearity using variance inflation factor (VIF)
statistics, but no multicollinearity between variables was found.
Various methods of model selection were then applied using the potential
covariates with each outcome while always including GFR groups in the
final model to determine if it continued to have a significant effect on
the outcome when adjusted for other covariates. This included stepwise
selection, backward selection, forward selection, and best subsets
selection using 0.15 as the entry criteria and 0.05 as the stay
criteria. The results from all methods were incorporated into making a
decision about the composition of the final model. Hazard ratios were
used to quantify the magnitude and direction of the effect of each
significant variable on the outcome.

\emph{Results}

Table 1 shows baseline characteristics of the patients with GFR
\textless{}60 ml/min (renal dysfunction) compared with patient with GFR
[?]60 ml/min. Over 98\% of the patient population were either African
Americans or Latinos. Table 1 also shows the statistically significant
differences in baseline characteristics. Table 2 shows incidence of
myocardial Ischemia, stroke, and MI stroke or death in patients with
renal dysfunction as compared to patients with GFR [?]60. Out of 339
patients with renal dysfunction, 56 (17\%) had MI, 72 (21\%) had stroke,
85 (25\%) died and 163 (48\%) had MI, Stroke or Death. In comparison,
out of 317 patients with GFR [?]60, 27 (9\%) patient had MI, 48 (15\%) had
stroke, 41 (13\%) died and 99 (31\%) had MI, stroke or death. Table 3
shows stepwise cox regression analysis for the time to the development
of MI, Stroke, Death and MI, stroke or Death (any event).

Renal dysfunction was an independent risk factor for MI (Hazard ratio
1.88 (1.17, 3.04); p=0.009). It also shows CAD is an independent risk
factor for MI (2.79 (1.78, 4.39); p\textless{}0.001) as shown in prior
studies. Renal dysfunction is an independent risk factor for death (HR
1.63 (1.11, 2.41); p=0.014). In addition, age (HR 1.31 (1.13, 1.51), P
value \textless{}0.001) and prior MI (HR 2.24 (1.46, 3.43);
p\textless{}0.001) are also independent risk factors for death as shown
in prior studies. Where renal dysfunction is not an independent risk
factor for stroke (HR 1.13 (0.77, 1.65); p=0.529), age (HR 1.31 (1.13,
1.51); p\textless{}0.001) and prior stroke (HR 1.99 (1.36, 2.92),
p=0.001) are independent risk factors for new stroke as demonstrated in
prior studies. Renal dysfunction is an independent risk factor for MI,
stroke or death (Hazard ratio 1.37 (1.05, 1.78); p=0.018). It also shows
that age (HR 1.32 (1.20, 1.46); p\textless{}0.001) and prior stroke (HR
1.47 (1.11, 1.94); p=0.007) are also an independent risk factors for
composite of these three events.

\emph{Discussion}

In 2014, 8.0\% of all Medicare Fee-For-Service beneficiaries had a
diagnosis of AF (28). In the 65 and older population, AF prevalence was
higher among males (10.5\%) than females (8.4\%) and was highest among
Non- Hispanic Whites (10.2\%), followed by American Indians/Alaska
Natives (5.9\%), Hispanics (5.0\%), Blacks/African Americans (5.1\%),
and Asian Pacific Islanders (4.9\%). The cause of these differences in
prevalence is unknown but recent study suggests that there may be some
genetic protection against AF in minority populations (29).

Several additional reports have evaluated the prevalence of AF in CKD
patients but few have studied if CKD in AF patients independently
increases MACE when adjusted for previously defined traditional risk
factors for MACE. Our study is one of the first to assess the effects of
CKD on MACE in an African American and Latino NVAF population and
provides evidence that a decreased GFR was an independent risk factor
for MI, Death and MI, stroke and death among these patients. Our data
reinforces other studies that have identified renal dysfunction as an
added predictor of MACE, although our data is unique in that it is
predominantly from a non-Caucasian population.

Different than other studies in non- African Americans and Latinos, our
data showed that a decreased GFR was not an independent risk factor for
stroke in our patient population. In a recent large prospective cohort
study of AF patients, Go et al found that a lower level of estimated
glomerular filtration rate was associated with a graded, increased risk
of ischemic stroke and other systemic embolism, independently of known
risk factors in AF (30). A study performed in Japan evaluated if CKD
constitutes a risk for stroke and it concluded that decreased kidney
function increases the risk of first symptomatic stroke events in a
general Japanese population (31). Piccini et al reported that adding
impaired renal function to standard stroke risk scoring scale was a
potent predictor for stroke and systemic embolism in a predominantly
white population (22).

Multiple studies have demonstrated that stroke rates are higher in AF
patients with renal dysfunction. Vazquez et al demonstrated a 9.8-fold
increased risk of ischemic stroke among patients undergoing dialysis who
had AF compared those who maintained sinus rhythm during dialysis (32).
In the U.S. Renal Data System study, patients with end-stage renal
failure and AF had a 1.8-fold higher rate of ischemic strokes, whereas
hemorrhagic stroke rates were comparable to end-stage renal failure
patients in sinus rhythm (33). Conversely, in the Rotterdam study (34),
decreased GFR did not significantly increase the risk of ischemic
stroke, but was a strong predictor of hemorrhagic stroke. Genovesi et al
demonstrated that AF was associated with greater total and
cardiovascular mortality among hemodialysis patients and was more
notable for cardiovascular than non-cardiovascular mortality (8).
Nakagawa et al demonstrated that combined eGFR and
CHADS\textsubscript{2} score could be an independent powerful predictor
of cardiovascular events and mortality in patients with NVAF (35).
Long-term mortality, cardiac events, and stroke risk were
\textgreater{}8 times higher when decreased eGFR was present with higher
CHADS\textsubscript{2} score ([?]2).

The mechanism by which chronic kidney disease (CKD) increases the risk
of MACE is not known. CKD increases vascular calcification,
inflammation, valve problems, and fluctuation in electrolytes,
sympathetic nervous system activation and modulation of renin
angiotensin system. Tanaka (36) noted an inverse relationship of eGFR to
thrombin-antithrombin (TAT) and fibrin D-dimer levels, both indexes of
thrombogenesis. Shlipak demonstrated that renal insufficiency was
independently associated with elevations in inflammatory and
pro-coagulant biomarkers (37). These findings lend support to the notion
that enhanced coagulation activation appears to be related to a
reduction in residual renal function in patients with AF (38).

A manual review of EMR was performed for all patients included in the
study to avoid false positives and negative. However, our study has
several limitations. It was completed at one center and was done
primarily on African American and Latino patient population. The
Latino/Hispanic population was not sub-stratified further and there have
been differences in prevalence in various subgroups (5). This was a
retrospective analysis of such patients. The contradictory result for
CKD being an independent risk factor for stroke could be due to our
unique patient population, or a relatively small sample size of patients
with paroxysmal AF mistakenly excluded from study.

A prospective study in minority AF patients with renal dysfunction
should be done in the future to provide further evidence regarding
ischemic neurological events in this patient population and verify our
findings of MACE.

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\item
  Shlipak MG, Fried LF, Crump C, et al. Elevations of inflammatory and
  procoagulant biomarkers in elderly persons with renal
  insufficiency.~\emph{Circulation} . 2003;107(1):87-92.
\item
  Tomura S, Nakamura Y, Doi M, et al. Fibrinogen, coagulation factor
  VII, tissue plasminogen activator, plasminogen activator inhibitor-1,
  and lipid as cardiovascular risk factors in chronic hemodialysis and
  continuous ambulatory peritoneal dialysis patients.~\emph{Am J Kid
  Dis} . 1996;27(6):848-854.
\end{enumerate}

\textbf{Table 1}- Baseline characteristics of patients with GFR
\textless{}60 vs. patients with GFR \selectlanguage{english}[?]60\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Variable}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{GFR \textless{}60} \textbf{N = 339}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{GFR [?]60} \textbf{N = 317}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{p value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age (years)\textsuperscript{*}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
73.6 \selectlanguage{ngerman}± 13.3\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
67.1 \selectlanguage{ngerman}± 15.4\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Gender\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.015\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Men\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
154 (45\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
174 (55\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Women\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
185 (55\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
143 (45\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
African-American\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
271 (80\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
258 (81\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.639\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Latino\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
61 (18\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
51 (16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.517\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27.5 (9.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27.6 (9.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.433\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
315 (93\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
255 (80\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Dyslipidemia\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
136 (40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
117 (37\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.383\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Smoking\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
116 (35\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
145 (46\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.003\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
DM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
134 (40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
85 (27\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CAD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
80 (24\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
56 (18\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.067\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PVD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (10\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27 (9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.506\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CHF\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
113 (34\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
90 (29\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.198\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Prior stroke\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
77 (23\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
54 (17\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.076\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CHADVasc2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18 (5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
41 (13\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textgreater{}1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
316 (93\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
254 (80\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Oral Hypogly\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
65 (19\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
43 (14\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.053\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Insulin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
46 (14\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aspirin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
140 (41\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
129 (41\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.850\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Plavix\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24 (7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.204\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Statins\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
124 (37\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
112 (35\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.739\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\selectlanguage{greek}Β-\selectlanguage{english}Blockers\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
155 (46\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
136 (43\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.447\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ACEI/ARB\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
146 (43\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
144 (45\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.543\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Coumadin/AC\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
133 (39\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
135 (43\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.383\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\% Time on AC\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
62.7 (43.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
60.4 (33.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.551\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Digoxin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
42 (12\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
37 (12\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.778\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Amiodarone\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.159\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BiDil\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
20 (6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.017\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CCB-DH\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
82 (24\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
64 (20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.218\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CCB-NonDH\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
45 (13\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25 (8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.026\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ACEI Angiotensin converting enzyme; ARB Angiotensin
receptor blocker; BMI body mass index; GFR glomerular filtration rate. *
Mean \selectlanguage{ngerman}± SD, Two-sample t-test + Median (IQR), Wilcoxon Rank Sum test N
(\%), Chi-square test otherwise\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ACEI Angiotensin converting enzyme; ARB Angiotensin
receptor blocker; BMI body mass index; GFR glomerular filtration rate. *
Mean \selectlanguage{ngerman}± SD, Two-sample t-test + Median (IQR), Wilcoxon Rank Sum test N
(\%), Chi-square test otherwise\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ACEI Angiotensin converting enzyme; ARB Angiotensin
receptor blocker; BMI body mass index; GFR glomerular filtration rate. *
Mean \selectlanguage{ngerman}± SD, Two-sample t-test + Median (IQR), Wilcoxon Rank Sum test N
(\%), Chi-square test otherwise\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ACEI Angiotensin converting enzyme; ARB Angiotensin
receptor blocker; BMI body mass index; GFR glomerular filtration rate. *
Mean \selectlanguage{ngerman}± SD, Two-sample t-test + Median (IQR), Wilcoxon Rank Sum test N
(\%), Chi-square test otherwise\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textbf{Table 2}- Incidence of myocardial Ischemia, stroke, and MI
stroke or death in patients with GFR \textless{}60 vs. patients with GFR
\selectlanguage{english}[?]60\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Outcome}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{GFR \textless{}60} \textbf{N = 339}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{GFR [?]60} \textbf{N = 317}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{p value*}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Myocardial infarction\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
56 (17\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27 (9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.002\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Stroke\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
72 (21\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
48 (15\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.044\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Death\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
85 (25\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
41 (13\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
MI, Stroke or Death\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
163 (48\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
99 (31\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Binomial logistic regression model\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
* Binomial logistic regression model\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
* Binomial logistic regression model\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
* Binomial logistic regression model\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: MI: Myocardial Infarction; GFR: Glomerular filtration
rate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: MI: Myocardial Infarction; GFR: Glomerular filtration
rate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: MI: Myocardial Infarction; GFR: Glomerular filtration
rate\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: MI: Myocardial Infarction; GFR: Glomerular filtration
rate\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3-} Cox Proportional Hazard Regression Analysis for the
Time to the Development of Myocardial Infarction, Stroke, Death, or any
of these events among patients with GFR \textless{}60 vs. patients with
GFR [?]60\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Outcome} & \textbf{Prognostic Factor} & \textbf{Hazard Ratio
(95\% CI)} & \textbf{P-value*}\tabularnewline
Myocardial infarction & GFR \textless{}60 & 1.88 (1.17, 3.04) &
0.009\tabularnewline
& CAD & 2.79 (1.78, 4.39) & \textless{}0.001\tabularnewline
Stroke & GFR \textless{}60 & 1.13 (0.77, 1.65) & 0.529\tabularnewline
& Age (per 10 years) & 1.31 (1.13, 1.51) &
\textless{}0.001\tabularnewline
& Prior stroke & 1.99 (1.36, 2.92) & \textless{}0.001\tabularnewline
Death & GFR \textless{}60 & 1.63 (1.11, 2.41) & 0.014\tabularnewline
& Age (per 10 years) & 1.43 (1.23, 1.66) &
\textless{}0.001\tabularnewline
& Oral hypoglycemics & 1.77 (1.15, 2.72) & 0.009\tabularnewline
& Insulin & 0.33 (0.13, 0.82) & 0.017\tabularnewline
& Myocardial infarction & 2.24 (1.46, 3.43) &
\textless{}0.001\tabularnewline
Any event & GFR \textless{}60 & 1.37 (1.05, 1.78) & 0.018\tabularnewline
& Age (per 1 year) & 1.32 (1.20, 1.46) & \textless{}0.001\tabularnewline
& Prior stroke & 1.47 (1.11, 1.94) & 0.007\tabularnewline
Cox proportional hazards regression model & * Cox proportional hazards
regression model & * Cox proportional hazards regression model & * Cox
proportional hazards regression model\tabularnewline
Abbreviations: GFR: Glomerular filtration rate; CAD: Coronary artery
disease & Abbreviations: GFR: Glomerular filtration rate; CAD: Coronary
artery disease & Abbreviations: GFR: Glomerular filtration rate; CAD:
Coronary artery disease & Abbreviations: GFR: Glomerular filtration
rate; CAD: Coronary artery disease\tabularnewline
\bottomrule
\end{longtable}

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